A set of NF-κB-regulated microRNAs induces acquired TRAIL resistance in lung cancer.
Authors
Jeon, YMiddleton, J
Kim, T
Laganà, A
Piovan, C
Secchiero, P
Nuovo, G
Cui, R
Joshi, P
Romano, G
Di Leva, G
Lee, B
Sun, H
Kim, Y
Fadda, P
Alder, H
Garofalo, Michela
Croce, C
Affiliation
Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210Issue Date
2015-06-30
Metadata
Show full item recordAbstract
TRAIL (TNF-related apoptosis-inducing ligand) is a promising anticancer agent that can be potentially used as an alternative or complementary therapy because of its specific antitumor activity. However, TRAIL can also stimulate the proliferation of cancer cells through the activation of NF-κB, but the exact mechanism is still poorly understood. In this study, we show that chronic exposure to subtoxic concentrations of TRAIL results in acquired resistance. This resistance is associated with the increase in miR-21, miR-30c, and miR-100 expression, which target tumor-suppressor genes fundamental in the response to TRAIL. Importantly, down-regulation of caspase-8 by miR-21 blocks receptor interacting protein-1 cleavage and induces the activation of NF-κB, which regulates these miRNAs. Thus, TRAIL activates a positive feedback loop that sustains the acquired resistance and causes an aggressive phenotype. Finally, we prove that combinatory treatment of NF-κB inhibitors and TRAIL is able to revert resistance and reduce tumor growth, with important consequences for the clinical practice.Citation
A set of NF-κB-regulated microRNAs induces acquired TRAIL resistance in Lung cancer. 2015, 112 (26):E3355-64 Proc Natl Acad SciJournal
Proceedings of the National Academy of SciencesDOI
10.1073/pnas.1504630112PubMed ID
26080425Type
ArticleLanguage
enISSN
1091-6490ae974a485f413a2113503eed53cd6c53
10.1073/pnas.1504630112
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